Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Nanoparticle-mediated cellular response is size-dependent

Abstract

Nanostructures of different sizes, shapes and material properties have many applications in biomedical imaging, clinical diagnostics and therapeutics1,2,3,4,5,6. In spite of what has been achieved so far, a complete understanding of how cells interact with nanostructures of well-defined sizes, at the molecular level, remains poorly understood. Here we show that gold and silver nanoparticles coated with antibodies can regulate the process of membrane receptor internalization. The binding and activation of membrane receptors and subsequent protein expression strongly depend on nanoparticle size. Although all nanoparticles within the 2–100 nm size range were found to alter signalling processes essential for basic cell functions (including cell death)7, 40- and 50-nm nanoparticles demonstrated the greatest effect. These results show that nanoparticles should no longer be viewed as simple carriers for biomedical applications, but can also play an active role in mediating biological effects. The findings presented here may assist in the design of nanoscale delivery and therapeutic systems and provide insights into nanotoxicity.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Specific interactions between Her–GNPs and ErbB2 receptors determine their internalization fate.
Figure 2: Dependence of ErbB2 receptor internalization on nanoparticle size.
Figure 3: Dependence of downregulation of membrane ErbB2 expression on nanoparticle size.
Figure 4: Influence of different-sized nanoparticles on downstream protein expression.

References

  1. Xia, Y. et al. One-dimensional nanostructures: Synthesis, characterization, and applications. Adv. Mater. 15, 353–389 (2003).

    CAS  Article  Google Scholar 

  2. Alivisatos, A. P. Semiconductor clusters, nanocrystals, and quantum dots. Science 271, 933–937 (1996).

    CAS  Article  Google Scholar 

  3. Elghanian, R., Storhoff, J. J., Mucic, R. C., Letsinger, R. L. & Mirkin, C. A. Selective colorimetric detection of polynucleotides based on the distance-dependent optical properties of gold nanoparticles. Science 227, 1078–1081 (1997).

    Article  Google Scholar 

  4. Cao, Y. C., Jin, R. & Mirkin, C. A. Nanoparticles with Raman spectroscopic fingerprints for DNA and RNA detection. Science 297, 1536–1540 (2002).

    Article  Google Scholar 

  5. Klostranec, J. & Chan, W. C. W. Quantum dots in biological and biomedical research: recent progress and present challenges. Adv. Mater. 18, 1953–1964 (2006).

    CAS  Article  Google Scholar 

  6. Hirsch, L. R. et al. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proc. Natl Acad. Sci. USA 100, 13549–13554 (2003).

    CAS  Article  Google Scholar 

  7. Datta, S. R., Brunet, A. & Greenberg, M. E. Cellular survival: a play in three Akts. Genes Dev. 13, 2905–2927 (1999).

    CAS  Article  Google Scholar 

  8. Ullrich, A. & Schlessinger, J. Signal transduction by receptors with tyrosine kinase activity. Cell 61, 203–212 (1990).

    CAS  Article  Google Scholar 

  9. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 103, 211–225 (2000).

    CAS  Article  Google Scholar 

  10. Dubois, P. M., Stepinski, J., Urbain, J. & Sibley, C. H. Role of the transmembrane and cytoplasmic domains of surface IgM in endocytosis and signal transduction. Eur. J. Immunol. 22, 851–857 (1992).

    CAS  Article  Google Scholar 

  11. Chithrani, B. D., Ghazani, A. A. & Chan, W. C. W. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett. 6, 662–668 (2006).

    CAS  Article  Google Scholar 

  12. Osaki, F., Kanamori, T., Sando, S., Sera, T. & Aoyama, Y. A quantum dot conjugated sugar ball and its cellular uptake. On the size effects of endocytosis in the subviral region. J. Am. Chem. Soc. 126, 6520–6521 (2004).

    CAS  Article  Google Scholar 

  13. Shortkroff, S., Turell, M., Rice, K. & Thornhill T. S. Cellular response to nanoparticles. Mater. Res. Soc. Symp. Proc. 704, W11.5.1–W11.5.6 (2002).

    Article  Google Scholar 

  14. Carter, P. et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc. Natl Acad. Sci. USA 89, 4285–4289 (1992).

    CAS  Article  Google Scholar 

  15. Rubin, L. & Yarden, Y. The basic biology of Her2. Ann. Oncol. 12, S3–S8 (2001).

    Article  Google Scholar 

  16. Geoghegan, W. D. & Ackerman, G. A. Adsorption of horseradish peroxidase, ovomucoid and anti-immunoglobulin to colloidal gold for the indirect detection of concanavalin A, wheat germ agglutinin and goat anti-human immunoglobulin G on cell surfaces at the electron microscopic level: a new method, theory and application. J. Histochem. Cytochem. 25, 1187–1200 (1977).

    CAS  Article  Google Scholar 

  17. Chithrani, D. B. & Chan, W. C. W. Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes. Nano Lett. 7, 1542–1550 (2007).

    CAS  Article  Google Scholar 

  18. Hommelgaard, A. M., Lerdrup, M. & van Deurs, B. Assocation with membrane protrusions makes ErbB2 an internalization-resistant receptor. Mol. Biol. Cell 15, 1557–1567 (2004).

    CAS  Article  Google Scholar 

  19. Ghitescu, L. & Bendayan, M. Immunolabeling efficiency of protein A–gold complexes. J. Histochem. Cytochem. 38, 1523–1530 (1990).

    CAS  Article  Google Scholar 

  20. Horrisberger, M. & Clerk, M. F. Labeling of colloidal gold with protein A. A quantitative study. Histochemistry 82, 219–223 (1985).

    Article  Google Scholar 

  21. Gao, H., Shi, W. & Freund, L. B. Mechanics of receptor-mediated endocytosis. Proc. Natl Acad. Sci. USA 102, 9469–9474 (2005).

    CAS  Article  Google Scholar 

  22. Andrews, N. C. Iron homeostasis: Insights from genetics and animal models. Nat. Rev. Genet. 1, 208–217 (2000).

    CAS  Article  Google Scholar 

  23. Austin, C. D. et al. Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics Trastuzumab and Geldanamycin. Mol. Biol. Cell 15, 5268–5282 (2004).

    CAS  Article  Google Scholar 

  24. Baulida, J., Kraus, M. H., Alimandi, M., Di Fiore, P. P. & Carpenter, G. All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired. J. Biol. Chem. 271, 5251–5257 (1996).

    CAS  Article  Google Scholar 

  25. Vieira, A. V., Lamaze, C. & Schmid, S. L. Control of EGF receptor signaling by clathrin-mediated endocytosis. Science 274, 2086–2089 (1996).

    CAS  Article  Google Scholar 

  26. Yakes, F. M. et al. Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt is required for antibody-mediated effects on 27, Cyclin D1, and antitumour action. Cancer Res. 62, 4132–4141 (2002).

    CAS  Google Scholar 

  27. Frens, G. Controlled nucleation for the regulation of the particle size in monodisperse gold suspensions. Nature 241, 20–22 (1973).

    CAS  Google Scholar 

  28. Bonnard, C., Papermaster, D. S. & Kiraehenbuhl, J. P. The streptavidin–biotin bridge technique: Applications in light and electron microscope immunocytochemistry, in Immunolabeling for Electron Microscopy, 95–111 (Elsevier, New York, 1984).

  29. Solomon, S. D., Bahadory, M., Jeyarajasingam, A. V., Rutkowsky, S. A. & Boritz, C. Synthesis and study of silver nanoparticles. J. Chem. Educ. 84, 322–325 (2007).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Financial support was provided by the Canadian Institutes of Health Research (W.C.W.C. and J.T.R.), Natural Sciences and Engineering Council of Canada (W.J., B.Y.S.K. and W.C.W.C.), Canadian Foundation for Innovation and Ontario Innovation Trust (W.C.W.C.), the Surgeon Scientist Program and the Ontario Ministry of Health (B.Y.S.K.). The authors wish to thank J. Klonstranec for helpful discussions, A. Manseur and T. Jennings for help with flow cytometry, B. Calvieri, S. Doyle and D. Holmyard with cell preparation for electron microscopy, and J. Oreopoulos from the Yip lab with confocal microscopy.

Author information

Authors and Affiliations

Authors

Contributions

W.J., B.Y.S.K. and W.C.W.C designed the experiments. W.J. and B.Y.S.K. performed the experiments and gathered the data. All authors discussed the results, co-wrote the paper and commented on the manuscript. W.J. and B.Y.S.K. contributed equally to this work.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jiang, W., Kim, B., Rutka, J. et al. Nanoparticle-mediated cellular response is size-dependent. Nature Nanotech 3, 145–150 (2008). https://doi.org/10.1038/nnano.2008.30

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nnano.2008.30

Further reading

Search

Quick links

Find nanotechnology articles, nanomaterial data and patents all in one place. Visit Nano by Nature Research